A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
NCT ID: NCT01578239
Last Updated: 2022-04-04
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
231 participants
INTERVENTIONAL
2012-09-06
2021-01-18
Brief Summary
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Detailed Description
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Objective tumor assessment in both groups was performed every 12+/-1 weeks from the randomization date according to RECIST Criteria until progression was centrally confirmed:
1. Any participants with progressive disease (confirmed by central review of CT/MRI scans) ceased the treatment/assessment period and proceeded to the long-term follow-up period for evaluation of survival and long-term safety.
2. All non-progressive participants continued treatment/assessments until the PFS primary endpoint was met (i.e. 74 evaluable and centrally confirmed disease progressions or death events). Once the Primary End-Point was reached:
1. Participants who received more than 76 weeks of treatment/assessment, stopped the study treatment (however somatostatin analogues could be received as subsequent treatment as per Investigator's discretion) but continued the long-term follow-up assessment for 5 years overall from the date of randomization of the last participant randomized.
2. The remaining randomized participants continued in the fixed 76-week treatment/assessment period unless progression occurred, then continued the long-term follow-up assessments for 5 years overall from the date of randomization of the last participant.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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177Lu-DOTA0-Tyr3-Octreotate
* 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died.
* Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi).
* Concomitant amino acids were given with each administration for kidney protection.
* 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.
* In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed.
Octreotide LAR
In the experimental arm, 30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died.
In the active comparator arm, 60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.
177Lu-DOTA0-Tyr3-Octreotate
Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.
Octreotide LAR
* 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.
* In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed.
Octreotide LAR
In the experimental arm, 30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died.
In the active comparator arm, 60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.
Interventions
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Octreotide LAR
In the experimental arm, 30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died.
In the active comparator arm, 60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.
177Lu-DOTA0-Tyr3-Octreotate
Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Ki67 index ≤ 20% (to be centrally confirmed).
3. Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to randomization in the study.
4. Patients ≥18 years of age.
5. Patients must have progressive disease based on RECIST Criteria, Version 1.1 while receiving an uninterrupted fixed dose of Octreotide LAR (20-30 mg/3-4 weeks). Disease progression must be centrally confirmed. In order to make the assessment, two CT (or MRI) scans are required. The oldest scan must not be older than 3 years from the date of randomization. The most recent scan must not be older than 4 weeks from the date of randomization. Both scans must be obtained while the patient is receiving the same fixed dose of Octreotide LAR (20-30 mg/3-4 weeks) with the following exceptions; 1) it is acceptable if the oldest scan is obtained within 12 weeks of the patient receiving a fixed dose regimen of Octreotide LAR (20-30 mg/3-4 weeks); AND 2) it is acceptable for either scan to be obtained before or during the time a patient receiving a fixed dose of Octreotide LAR has switched to an equivalent dose of short acting Octreotide for up to 6 weeks in order to obtain an OctreoScan®, provided the patient returns to the Octreotide LAR fixed dose after the OctreoScan® has been obtained.
6. Confirmed presence of somatostatin receptors on all target lesions (for target/non-target/measurable lesions definition see §Appendix 2, Section 1 and 2, RECIST Criteria, Version 1.1) documented by CT/MRI scans, based on positive OctreoScan® imaging within 24 weeks prior to randomization in the study (to be centrally confirmed). The OctreoScan® should be one that was performed while the patient was on a fixed dose of Octreotide LAR. If a patient has had an OctreoScan® performed while Octreotide LAR treatment-naïve, the patient must have a repeat OctreoScan® performed after 3 months of Octreotide LAR treatments before entering the clinical study to prove that the index lesions or new lesions still meet the criteria for inclusion. It is acceptable to have patients temporarily switched to Octreotide s.c. (up to six weeks) in order to obtain an OctreoScan®, provided they return to the same fixed dose of Octreotide LAR prior to the scan.
7. The tumour uptake observed in each target lesion (for target/non-target/measurable lesions definition see §Appendix 2, Sections 1 and 2, RECIST Criteria, Version 1.1) using OctreoScan® must be ≥ normal liver uptake observed on planar imaging (to be centrally confirmed) (§Appendices 5 and 6).
8. Karnofsky Performance Score (KPS)\>=60.
9. Presence of at least 1 measurable site of disease.
10. \[Applicable only for France\] All patients included in the trial must be affiliated with a social security regime or be a beneficiary of the same in order to be included in the study.
Exclusion Criteria
2. Hb concentration \<5.0 mmol/L (\<8.0 g/dL); WBC \<2x109/L (2000/mm3); platelets \<75x109/L (75x103/mm3).
3. Total bilirubin \>3 x ULN.
4. Serum albumin \<3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy or lactation.
6. For female patients of childbearing potential (defined as \< 2 years after last menstruation and not surgically sterile) and male patients, who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) as defined in §Appendix 7.
7. Treatment with \>30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to randomization in the study.
8. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
9. Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to randomization in the study.
10. Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
11. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
12. Uncontrolled congestive heart failure (NYHA II, III, IV).
13. Uncontrolled diabetes mellitus as defined by a fasting blood glucose \>2 ULN.
14. Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTA0-Tyr3-Octreotate, unless the tumour uptake on target lesions observed by OctreoScan® imaging during continued Octreotide LAR treatment is at least as high as normal liver uptake observed by planar imaging.
15. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
16. Prior external beam radiation therapy to more than 25% of the bone marrow.
17. Current spontaneous urinary incontinence.
18. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
19. Patients who have not provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
20. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
21. Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days are excluded from participation in this trial.
18 Years
ALL
No
Sponsors
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Advanced Accelerator Applications
INDUSTRY
Responsible Party
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Principal Investigators
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Novartis Pharmaceuticals
Role: STUDY_DIRECTOR
Novartis Pharmaceuticals
Locations
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Cedars-Sinai Medical Center Samuel Oschin Cancer Center
Los Angeles, California, United States
Stanford Cancer Center
Palo Alto, California, United States
Moffitt Cancer Center
Tampa, Florida, United States
Northwestern Medical Faculty Foundation
Chicago, Illinois, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Mayo Clinic
Rochester, Minnesota, United States
Duke University Medical Center
Durham, North Carolina, United States
Kettering Medical Center
Kettering, Ohio, United States
Perelman Center for Advanced Medicine
Philadelphia, Pennsylvania, United States
Henry-Joyce Cancer Clinic
Nashville, Tennessee, United States
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Excel Diagnostics and Nuclear Oncology Center
Houston, Texas, United States
Digestive Oncology, Leuven Cancer Institute
Leuven, Brabant Flamand, Belgium
Centre Hospitalier Lyon-Sud
Lyon, Auvergne-Rhône-Alpes, France
Institut Claudius Regaud
Toulouse, Midi-Pyrénées, France
Hotel Dieu/CHU Nantes
Nantes, Pays de la Loire Region, France
Hôpital la Timone /CHU Marseille
Marseille, Provence-Alpes-Côte d'Azur Region, France
Hôpital Beaujon AP-HP
Clichy, , France
Institut Gustave Roussy
Villejuif, Île-de-France Region, France
Klinikum Rechts Isar, Nuclear Medicine
Munich, Bavaria, Germany
Universitätsmedizin Mainz, Medizinische Klinik I Schwerpunkt Endokrinologie
Mainz, Rhineland-Palatinate, Germany
Zentralklinik Bad Berka
Bad Berka, Thuringia, Germany
Charité, Virchow-Klinikum, Gastroentrology, Hepatology & Endocrinology
Berlin, , Germany
Istituto Oncologico Romagnolo per lo Studio dei Tumori
Meldola, Emilia-Romagna, Italy
IEO Istituto Europeo di Oncologia
Milan, Lombardy, Italy
Presidio Osp. Di Macerata
Macerata, The Marches, Italy
Azienda Ospedaliero - Universitaria Pisana (Presidio Ospedaliero S. Chiara)
Pisa, Tuscany, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, , Italy
Università "Sapienza" di Roma, Facoltà di Medicina e Psicologia, Ospedale S. Andrea-Roma
Roma, , Italy
Centro Hospitalar e Universitario de Coimbra
Coimbra, Centro, Portugal
Instituto Português de Oncologia
Porto, Norte, Portugal
University Hospital of Bellvitge
Hospitalet de Llobregat (Barcelona), Catalonia, Spain
Ramon y Cajal University Hospital
Madrid, , Spain
University of Oxford
Oxford, South East England, United Kingdom
Beatson Oncology Centre
Glasgow, , United Kingdom
Royal Free Hospital
London, , United Kingdom
Imperial College Healthcare Trust, Hammersmith Hospital
London, , United Kingdom
The Christie NHS foundation Trust
Manchester, , United Kingdom
Countries
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References
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Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Dec;22(12):1752-1763. doi: 10.1016/S1470-2045(21)00572-6. Epub 2021 Nov 15.
Strosberg J, Kunz PL, Hendifar A, Yao J, Bushnell D, Kulke MH, Baum RP, Caplin M, Ruszniewski P, Delpassand E, Hobday T, Verslype C, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Paganelli G, Severi S, Morse M, Metz DC, Ansquer C, Courbon F, Al-Nahhas A, Baudin E, Giammarile F, Taieb D, Mittra E, Wolin E, O'Dorisio TM, Lebtahi R, Deroose CM, Grana CM, Bodei L, Oberg K, Polack BD, He B, Mariani MF, Gericke G, Santoro P, Erion JL, Ravasi L, Krenning E; NETTER-1 study group. Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study. Eur J Nucl Med Mol Imaging. 2020 Sep;47(10):2372-2382. doi: 10.1007/s00259-020-04709-x. Epub 2020 Mar 2.
Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E; NETTER-1 Study Group. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018 Sep 1;36(25):2578-2584. doi: 10.1200/JCO.2018.78.5865. Epub 2018 Jun 7.
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Oberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427.
Related Links
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Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177 Lu-Dotatate in the Phase III NETTER-1 Trial (J Clin Oncol
. 2018 Sep 1;36(25):2578-2584)
Other Identifiers
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2011-005049-11
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
CAAA601A12301
Identifier Type: OTHER
Identifier Source: secondary_id
AAA-III-01
Identifier Type: -
Identifier Source: org_study_id
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